The recent introduction of a highly pathogenic strains of West Nile Virus (WNV) into naive populations in Europe, Israel and the United States have resulted in epidemics with a marked increase in both the number of reported cases and the severity of disease compared to previous outbreaks. The increased virulence of the recently emerged strain of WNV is further complicated by the fact that antiviral therapies and vaccines are not currently available for use in humans. The molecular mechanisms for the increase in pathogenesis of WNV are currently unknown but are likely to include novel viral-host interactions that allow the virus to overcome or evade the host innate and/or adaptive immune response. Our preliminary studies indicate that pathogenic and nonpathogenic strains of WNV differ dramatically in their interactions with innate antiviral programs. This suggests that the comparison of the antiviral responses to pathogenic and nonpathogenic strains of WNV will provide key insights in viral factors involved in WNV- mediated pathogenesis. The specific aim of this proposal are (1) Determination of the pattern recognition receptors involved in detecting pathogenic and nonpathogenic strains of WNV (2) Identification of agonists of the innate antiviral response generated during WNV infection and (3) Determination of viral factors responsible for WNV virulence. A greater understanding of how strains with difference virulence phenotypes interact with the innate antiviral response will aid in the development of effective vaccines and therapeutic agents. PUBLIC HEALTH RELEVANCE: The ability of the cell to detect and respond to an invading pathogen is critical to its ability to defend itself against infections. This proposal will examine how cells detect West Nile virus infections and conversely the mechanisms the virus utilizes to control the cellular environment.